Significant advances have been achieved in our understanding of both the humoral and cellular immune response in HIV infection, however the correlates of protection against disease progression have still not been defined. Several lines of evidence suggest that although both CD8+ T cells and neutralizing antibodies seem to play a critical role in suppressing viral replication in vitro, vaccines that induce these responses do not seem to induce protective immunity. HIV-1 infection is associated with a dramatic hypergammaglobulinemia. Despite the induction of these large quantities of antibodies, broadly neutralizing antibodies only seem to develop following years of infection, and always seem to lag behind and poorly neutralize the contemporaneous infecting virus. However a small number of studies have demonstrated that in addition to neutralizing antibodies, non-neutralizing antibodies that can induce cytolytic activity, such as those that induce antibody-dependent cellular cytotoxicity (ADCC), may also play a protective role in the control of HIV-1 infection. ADCC inducing antibodies are detectable as early as acute HIV-1 infection, can be isolated from mucosal sites, and correlate independently of other effector functions with better disease outcome. Furthermore, novel data from the simian model of infection suggests that neutralizing antibodies may largely elicit their protective role in vivo via the induction of ADCC activity. However human studies, aimed at defining the role of ADCC in the control of HIV-1 infection, have been performed on small numbers of poorly characterized patient populations, using varied and incomparable assays. Given the association of ADCC with slower HIV-1 disease progression, data from the SIV model demonstrating that ADCC may be important in preventing infection, the capacity of ADCC inducing antibodies to elicit and focus the effector functions of cells of the innate immune system, the fact that non-neutralizing Abs are flexible and can target multiple epitopes in the HIV envelope gene products, their critical nature in the immune response in the context of other infections and cancer models, and the ease with which antibodies can be induced via vaccination, it is plausible that protective antibodies with cytolytic functions could play a critical role in containing HIV-1 replication. It is therefore imperative that we begin to define the role of cytolytic antibodies to determine whether the induction of these immune responses can improve control of HIV-1 replication in vivo. Thus this application aims to comprehensively define the role of cytolytic ADCC inducing antibody responses in HIV-1 infection and to determine whether the induction of these responses should be a priority in our efforts to design an effective vaccine. PUBLIC HEALTH RELEVANCE: Both killer- T cells and antibodies that block viral infection (neutralizing antibodies) seem to play a critical role in suppressing viral replication in vitro, but vaccines that induce these responses do not induce protection against HIV-1 disease progression. In contrast, non-neutralizing antibodies that bridge the adaptive (B cells) to the innate immune response, via the induction of cytolytic activity by cells of the innate immune system by antibody dependent cellular cytotoxicity (ADCC), have been identified in patients as early as acute HIV-1 infection and correlate significantly with better disease outcome. Given the critical nature of non-neutralizing antibodies in slower HIV-1 disease progression, their flexibility in targeting multiple regions on the HIV envelope protein, as well as their critical role in protection against other pathogenic infections and cancers, it is plausible that antibodies with cytolytic functions could play a central role in controlling HIV-1 replication as well. This proposal therefore aims to define the role of ADCC in HIV- 1 infection to determine whether the generation of these responses should be a priority in our efforts to design an effective prophylactic or therapeutic vaccine.